Steroids for the treatment of hypercholesterolemia

Abstract

Steroids of the formula <IMAGE> I wherein n represents the number 2, 3 or 4; R1 represents hydrogen, lower-alkyl or lower-alkylidene; R2, R3 and R4 represent hydrogen or lower-alkyl and the dotted C-C bonds in the 5(6)-, 7(8)-, 22(23)-, 24(28)- and 25(26)-position are optional, whereby the B-ring can contain only one double bond and the side-chain is either saturated or is mono-unsaturated or is di-unsaturated in the 22(23), 25(26)-position; and whereby R1 is lower-alkyl or lower-alkylidene when a 5(6)-double bond is present, n is 2 and R2, R3 and R4 are methyl, and pharmaceutically acceptable salts of these steroids have activity inhibiting the intestinal resorption of cholesterol. They can be manufactured from steroids which are otherwise substituted in the 3 beta -position.

I claim: 
     
       1. Steroids of the formula ##STR11## wherein n is 2,3 or 4; R 1  is hydrogen, or lower-alkyl; R 2 , R 3  and R 4  are hydrogen or lower-alkyl and the dotted C--C bonds in the 5(6)-, 7(8)-, 22(23)-, and 25(26)-positions are optional, with the provisos that the B-ring contains only one double bond and the side-chain is either saturated, mono-unsaturated, or di-unsaturated in the 22(23) and 25(26)-positions; and with the further proviso that R 1  is lower-alkyl when a 5(6)-double bond is present, n is the number 2 and R 2 , R 3  and R 4  are methyl, and pharmaceutically acceptable salts of these steroids.   
     
     
       2. Steroids according to claim 1 wherein R 1  is ethyl. 
     
     
       3. Steroids according to claim 1 wherein R 2 , R 3  and R 4  are lower-alkyl. 
     
     
       4. Steroids according to claim 3 wherein R 2 , R 3  and R 4  are methyl. 
     
     
       5. Steroids according to claim 1 wherein n is 2. 
     
     
       6. Saturated steroids according to claim 1. 
     
     
       7. 5(6)- and 22(23)-di-unsaturated steroids according to claim 1. 
     
     
       8. Steroids according to claim 1 wherein R 1  is hydrogen or lower-alkyl; R 2 , R 3  and R 4  are lower-alkyl; and, n is 2. 
     
     
       9. Fully saturated steroids according to claim 8. 
     
     
       10. 5(6)- and 22(23)-di-unsaturated steroids according to claim 8. 
     
     
       11. Steroids according to claim 8 wherein R 1  is ethyl and R 2 , R 3  and R 4  are methyl. 
     
     
       12. Saturated steroids according to claim 11. 
     
     
       13. 5(6)- and 22(23)-di-unsaturated steroids according to claim 11. 
     
     
       14. In accordance with claim 12, the compound 3β-Stigmastanyloxy-phosphorylcholine. 
     
     
       15. In accordance with claim 13, the compound Stigmasta-5,22-dien-3β-yloxy-phosphorylcholine. 
     
     
       16. A method for treatment of hypercholesterolaemia which comprises administering to a host requiring such treatment a pharmaceutically effective amount of a steroid of the formula ##STR12## wherein n is 2, 3 or 4; R 1  is hydrogen, or lower-alkyl; R 2 , R 3  and R 4  are hydrogen or lower-alkyl and the dotted C--C bonds in the 5(6)-, 7(8)-, 22(23)-, and 25(26)-positions are optional, with the provisos that the B-ring contains only one double bond and the side-chain is either saturated, mono-unsaturated, or di-unsaturated in the 22(23) and 25(26)-positions; and with the further proviso that R 1  is lower-alkyl when a 5(6)-double bond is present, n is the number 2 and R 2 , R 3  and R 4  are methyl, or a pharmaceutically acceptable salt thereof.   
     
     
       17. A process for the manufacture of a steroid of the formula ##STR13## wherein n is 2,3 or 4; R 1  is hydrogen, or lower-alkyl; R 2 , R 3  and R 4  are hydrogen or lower-alkyl and the dotted C--C bonds in the 5(6)-, 7(8)-, 22(23)-, and 25(26)-positions are optional, with the provisos that the B-ring contains only one double bond and the side-chain is either saturated, mono-unsaturated, or di-unsaturated in the 22(23) and 25(26)-positions; and with the further proviso that R 1  is lower-alkyl when a 5(6)-double bond is present, n is the number 2 and R 2 , R 3  and R 4  are methyl, or a pharmaceutically acceptable salt thereof, which process comprises reacting a compound of the formula ##STR14## with a salt of the formula ##STR15## wherein n, R 1 , R 2 , R 3 , R 4  and the dotted C--C bonds are as hereinbefore defined; X and Y are chlorine, bromine or iodine or X and Y together are a 1,2-dimethylethylenedioxy residue and Z is lower-alkylsulphonyloxy, arylsulphonyloxy, perchloryloxy, chloro, bromo or iodo,   in the presence of a base and hydrolyzing the product.   
     
     
       18. A process for the manufacture of a steroid of the formula ##STR16## wherein n is 2, 3 or 4; R 1  is hydrogen, or lower-alkyl; R 2 , R 3  and R 4  are hydrogen or lower-alkyl and the dotted C--C bonds in the 5(6)-, 7(8)-, 22(23)-, and 25(26)-positions are optional, with the provisos that the B-ring contains only one double bond and the side-chain is either saturated, mono-unsaturated, or di-unsaturated in the 22(23) and 25(26)-positions; and with the further proviso that R 1  is lower-alkyl when a 5(6)-double bond is present, n is the number 2 and R 2 , R 3  and R 4  are methyl, or a pharmaceutically acceptable salt thereof, which process comprises reacting a compound of the formula ##STR17## wherein X is a metallized hydroxy group and Y is a group of the formula Hal--(CH 2 ) n  --O, wherein Hal is chlorine, bromine, or iodine and n is as hereinbefore defined, or in which X and Y together form an ethylenedioxy residue with an amine of the formula N(R 2 ,R 3 ,R 4 ) and wherein R 1 , R 2 , R 3  and R 4  are as hereinbefore defined.   
     
     
       19. A process for the manufacture of a steroid of the formula ##STR18## wherein n is 2, 3 or 4; R 1  is hydrogen, or lower-alkyl; R 2 , R 3  and R 4  are hydrogen or lower-alkyl and the dotted C--C bonds in the 5(6)-, 7(8)-, 22(23)-, and 25(26)-positions are optional, with the provisos that the B-ring contains only one double bond and the side-chain is either saturated, mono-unsaturated, or di-unsaturated in the 22(23) and 25(26)-positions; and with the further proviso that R 1  is lower-alkyl when a 5(6)-double bond is present, n is the number 2 and R 2 , R 3  and R 4  are methyl, or a pharmaceutically acceptable salt thereof, which process comprises cleaving off the amino protecting group in a compound of the formula ##STR19## in which X is a metallized hydroxy group and Y is residue of the formula ##STR20## wherein one of R 21  and R 31  is an amino protecting group and the other is the same as R 2 , or R 21  and R 31  together with the N-atom are a protected amino group, and n and R 2  are as hereinbefore defined.   
     
     
       20. A composition comprising a therapeutically effective amount of a steroid of the formula ##STR21## wherein n is 2, 3 or 4; R 1  is hydrogen, or lower-alkyl; R 2 , R 3  and R 4  are hydrogen or lower-alkyl and the dotted C--C bonds in the 5(6)-, 7(8)-, 22(23)-, and 25(26)-positions are optional, with the provisos that the B-ring contains only one double bond and the side-chain is either saturated, mono-unsaturated, or di-unsaturated in the 22(23) and 25(26)-positions; and with the further proviso that R 1  is lower-alkyl when a 5(6)-double bond is present, n is the number 2 and R 2 , R 3  and R 4  are methyl, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier material.   
     
     
       21. A composition in accordance with claim 20, wherein the 5(6)- and 22(23)-positions are unsaturated. 
     
     
       22. A composition in accordance with claim 21, wherein the compound of formula I is stigmasta-5,22-dien-3β-yloxy-phosphorylcholine. 
     
     
       23. A composition in accordance with claim 20, wherein the compound of formula I is saturated. 
     
     
       24. A composition in accordance with claim 23, wherein the compound of formula I is 3β-stigmastanyloxy-phosphorylcholine.